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Protein language models reveal evolutionary constraints on synonymous codon choice.

Helen Sakharova1, Liana F Lareau1,2,3

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Summary

Evolutionary pressures shape codon usage, influencing translation speed and protein production. This study reveals cotranslational localization and accuracy, not folding, as key drivers of codon choice constraints in yeast.

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Area of Science:

  • Molecular Biology
  • Evolutionary Biology
  • Genomics

Background:

  • The genetic code shows preferences for synonymous codons, driven by evolutionary pressures.
  • Ribosome translation speed varies for different codons, impacting protein production.
  • The molecular basis for evolutionary constraints on codon choice remains largely unknown.

Purpose of the Study:

  • To investigate evolutionary constraints on synonymous codon choice in yeast.
  • To determine the molecular drivers of codon usage bias.
  • To predict codon choice from protein sequence using a protein language model.

Main Methods:

  • Utilized a protein language model to predict codon choice from amino acid sequences.
  • Integrated implicit information on protein position and structure.
  • Performed a genome-wide screen of synonymous codon substitutions in yeast.

Main Results:

  • Identified several hundred synonymous variants affecting yeast fitness.
  • Demonstrated that most positions have no measurable effect on growth.
  • Showed that cotranslational localization and translational accuracy are major drivers of selective pressure.

Conclusions:

  • Codon constraints can be predicted from protein sequence alone.
  • Cotranslational localization and translational accuracy are key evolutionary pressures on codon choice.
  • Unappreciated biological constraints on codon choice were revealed through combined evolutionary and experimental approaches.